Gene therapy challenges and the solutions in sight

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Federico Mingozzi
Dr. Federico Mingozzi is the CSO of Spark Therapeutics, the company behind Luxturna – the world’s first FDA-approved gene therapy for a genetic disease. Though we like to focus on success stories like Luxturna, the reality is that gene therapy is a new modality, and the field is still developing. We spoke to Dr. Mingozzi about some of the technical challenges currently hampering progress in gene therapy, and how people are working together to overcome these hurdles.

This article was part of a series on gene therapy in the lead up to Science for health 2022, where Dr. Federico Mingozzi gave a talk on overcoming technical challenges in gene therapy.

Q: Gene therapy faces a lot of technical challenges, starting with the delivery itself. Could you tell us a bit about this?

Federico Mingozzi: “Despite the successes in the clinic, some challenges with gene therapy remain. Many of these – particularly regarding efficiency and toxicity associated with high vector doses – are due to the fact that some of our tools aren’t fully optimized for targeting specific tissues. For example, in a disease like Duchenne muscular dystrophy, where you’re trying to target muscle tissue, vectors used to deliver the DNA payload may end up off-target in the liver. This can then trigger liver toxicity, which is something we’ve seen in clinical trials, particularly where very large doses of AAV were used systemically. Similarly, if you’re trying to target the central nervous system, current tools aren’t very efficient at crossing the blood-brain barrier, meaning that high-doses are required and the vector ends up in other tissues across the body.

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“There are multiple solutions in the works. For systemic delivery, there are a lot of ongoing efforts to develop better, more targeted AAV vectors. People are creating viral vectors that are better at reaching specific types of cells, while avoiding off-target organs like the liver. In addition to these next-gen viral vectors, there are also novel delivery technologies still in the early stages of development – things like lipid nanoparticles and bioconjugates. Other strategies are directed at limiting toxicities – these include complement inhibition, or different immunomodulatory regimens. The result of all these efforts will not only help us to avoid toxicity issues, but also to decrease the therapeutic dose required for effective gene therapy, which should have a broad impact on both the safety of the products and the cost of goods during manufacturing.

“I think it’s also important to note that in the same timeframe that some trials have struggled with specificity and toxicity, others have gone extremely well. In the past few years, we’ve had safe and efficacious gene therapies approved that bring remarkable benefit to patients! The benefits of gene therapies ­and what they can deliver in terms of patient outcomes – it’s incredible! Sometimes you lose sight of that, amidst all the challenges.”

Q: It sounds like there is a lot of concurrent progress happening, both with the vectors and the payloads. Is that innovation taking place within the gene therapy companies, or is it a combined effort with academia?

Federico Mingozzi: “A lot of the work is definitely still happening in academia. There are also many companies that are fully dedicated to improving delivery platforms, even without a therapeutic pipeline of their own. The Boston-based company Dyno Therapeutics, for example, is exclusively focused on developing novel viral vectors, while other companies specialize in optimizing gene therapy payloads. I think there is a lot of collaboration happening in this field, because everyone has realized we need to work together to improve the current platforms.

“The success of the field depends on the success of all the individual players. We understand that we need to help each other out, if we’re going to overcome the big hurdles of gene therapy.” – Federico Mingozzi

“There are also a lot of efforts taking place in this precompetitive space, where companies – even competitors – are tackling some of these issues together. One example is the Innovative Medicines Initiative ARDAT, which is an EU consortium of industry and academia addressing issues like AAV immunogenicity. There’s also the Bespoke Gene Therapy Consortium by the Accelerating Medicines Partnership (from the NIH and FDA), which is active across Europe and the US. These kinds of initiatives are fantastic, in my opinion, because the truth is: the success of the field depends on the success of all the individual players. We understand that we need to help each other out, if we’re going to overcome the big hurdles of gene therapy. We owe this to patients.”

Q: Are there specific challenges associated with gene therapy manufacturing?

Federico Mingozzi: “Definitely: the vast majority of the delays in gene therapy product approvals are related to manufacturing. There are a few reasons for this. Firstly, the regulatory environment around therapeutics manufacturing has changed a lot, with more oversight by regulators and stricter requirements regarding product quality. For gene therapies specifically, the purity of the product is one of the most important considerations, because contaminants can drive toxicities. So manufacturing technologies and analytical tools need to evolve accordingly.”

“The second manufacturing challenge relates to scalability and cost. With gene therapies starting to target more common diseases, and to make gene therapies more affordable in general, we need to increase yields and tackle the high cost of goods associated with this class of drugs. There is a lot of exciting innovation happening in the space to address these issues, including developing more scalable production methods, like suspension or producer cell lines.”

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“The last challenge relates to comparability: ensuring that the basic product attributes remain the same even if there is a change to the manufacturing process. Since gene therapy is such a new therapeutic modality, and manufacturing platforms aren’t always well established, in some cases clinical trials start with one manufacturing platform which is then improved over time. This is an example of a case in which potential issues related to comparability are encountered, which can result in delays in obtaining regulatory approval. Large CDMOs have invested heavily in this space, but manufacturing challenges are still a bottleneck for new gene therapies.”

Q: Are there any other major hurdles blocking progress in the gene therapy space?

Federico Mingozzi: “One complex question for the field concerns pricing. For example, how do we afford to keep making gene therapies for ultra-rare diseases? We know there have been effective therapies for rare diseases developed by academics, which companies haven’t picking them up because there’s no profitability. How do we fix this? And how do we set prices for the larger indications as well, where one dose is potentially enough for a lifetime? There are a lot of discussions ongoing to tackle these questions, and progress is also happening on this front.”

“We have to be patient and remember the reason we’re putting in all this hard work: because we know that gene therapies can truly transform people’s lives.” – Federico Mingozzi

“Which brings me to my final point: I think it’s important to keep in mind is that there is a lot of innovation that still needs to happen in this space. Gene therapy is a new modality, and new modalities take time to perfect. This has also been true for other classes of therapeutics, like monoclonal antibodies. A lot of people are working together to improve the different aspects of this field, from technical challenges to logistical hurdles and more. We have to be patient and remember the reason we’re putting in all this hard work: because we know that gene therapies can truly transform people’s lives.”